Implantable drug delivery devices are a new type of medicinal therapy. After implantation, the devices release a drug at a predictable rate directly to the tissue that will benefit from treatment. Typically, the implantable drug delivery devices are made up of a pharmaceutical agent (active agent) coated with a biocompatible, biodegradable material called a matrix. The device may be implanted into the tissue where the drug is to act. With time, the drug can be released into the tissue by diffusion and/or biodegradation of the coating. This localizes the drug specifically to the tissue where it is necessary, having considerable advantages including control over the drug delivery and the ability to use drug formulations that cannot be delivered orally or by injection. The result is improved efficacy, reduced toxicity, and improved patient compliance and convenience.
The active agent can be any drug or pharmaceutical preparation; for example, an anti-cancer agent. Delivery of the anti-cancer drug specifically at the site of the cancer will reduce the potential side effects or damage to non-cancerous tissue. The coating of the implantable drug delivery device is usually a polymeric matrix that is composed of a poly-a-amino acid, which naturally occurs in humans. With time, the matrix will degrade in the body due to natural processes of the host. However, it is not mandatory that the matrix degrade in the host, and other biomaterials are possible. Common shapes of implantable drug delivery devices include but are not limited to microspheres and rods, among others.
There are different modes of action of implantable drug delivery devices, depending on the system. The most common implantable drug delivery device may work through controlled release mechanisms, environmentally responsive systems, or biodegradable systems. In a controlled release mechanism, a drug or other active agent diffuses out from the polymer that forms the device. The combinations of polymer matrices and bioactive agents chosen must allow for the drug to diffuse through the pores or macromolecular structure of the polymer upon introduction of the delivery system into the biological environment without inducing any change in the polymer itself. In an environmentally responsive system, the device is designed so that it is incapable of releasing its agent or agents until it is placed in an appropriate biological environment. An example of this is a hydrogel that swells when in contact with water or other bodily fluids. In biodegradable systems, the device degrades within the body as a result of natural biological processes. This eliminates the need to remove a drug delivery system after release of the active agent has been completed. The future directions of implantable drug delivery devices lie in the area of responsive delivery systems, where drugs or active agents will be delivered through implantable devices in response to a specific biological function.
One example of an implantable drug delivery device is a drug-eluting stent, which is used to prevent artery collapse. Coronary arteries are the network of arteries that provide blood flow to the heart tissue itself. The arteries deliver the oxygen and vital nutrients the heart needs to function properly. In youth, coronary arteries are smooth, elastic, hollow tubes through which blood can flow freely. As aging occurs, fat builds up on the walls of the coronary arteries, causing slight injury to the blood vessel walls. In an attempt to heal the injury, the cells of the blood vessel walls (endothelial cells) release chemicals that attract other substances traveling through the blood stream, such as inflammatory cells, proteins and calcium. The fat and other substances combine to form a material called plaque, which builds up until it eventually clogs and narrows the artery, a process called atherosclerosis. Coronary artery disease (CAD) is when the arteries of the heart become atherosclerotic, restricting bloodflow to the heart muscle itself.
If the heart does not get enough oxygen and nutrients due to reduced blood flow in the blocked arteries, one may experience chest pain called angina. When one or more of the coronary arteries are completely blocked, the result is a heart attack, which is injury to the heart muscle. Typically, most individuals with coronary heart disease might show no evidence of disease for decades as the disease progresses. There may be no indication of disease before the first onset of symptoms, which is often a sudden heart attack.
Interventional procedures such as balloon angioplasty and stent placement are common methods to treat CAD. These procedures are considered non-surgical because they are done by a cardiologist through a catheter inserted into a blood vessel, rather than by a surgeon. In the balloon angioplasty procedure, a small balloon at the tip of the catheter is inserted near the blocked or narrowed area of the coronary artery. When the balloon is inflated, the fatty plaque or blockage is compressed against the artery walls and the diameter of the blood vessel is widened (dilated) to increase blood flow to the heart. Sometimes after this procedures restenosis or artery collapse occurs, where the artery becomes reblocked. To overcome this, in most cases, balloon angioplasty is performed in combination with the placement of a stent. A stent is a small, metal, mesh tube that acts as a scaffold to provide support inside the coronary artery to prevent restenosis. A balloon catheter is used to insert the stent into the narrowed artery, and the stent stays in place permanently. The artery heals around the stent, somewhat diminishing restenosis.
Although stents seemed to prevent artery collapse, restenosis was still a problem leading to the development of drug-eluting stents. A drug-eluting stent is a normal metal stent that has been coated with a pharmacologic agent (drug) that is known to interfere with the process of restenosis. Drug-eluting stents contain a medication that is actively released at the stent implantation site. There are three major components to a drug-eluting stent: the bare metal stent itself, coating on the stent (typically polymetric) to deliver the drug to the arterial wall, and the drug itself.
Pharmaceutical companies who design drug delivery devices must be able to indicate efficaciousness of an implantable drug delivery device to the FDA. Some issues that must be addressed include the rate of drug delivery, the diffusion of the drug, the affect of the drug on a tissue, and the degradation of the matrix, among others. Companies that produce drug-eluting stents are interested in ascertaining how the stent (including drug and delivery-mechanism) affects the tissue. The current standard is for pathologists to study the tissue after placement of the stent. The pathologist looks at three main factors: histology, morphology, and morphometry. Histology is the study of thin sections of tissue. Pathologists will look at arterial tissue sections, stained with appropriate histological stain, to be able to visualize the vascular structure of the tissue. Such structures include the different layers of the artery: the neointima, internal elastic lamina (IEL), media, external lumina (EEL), and adventitia.
Morphology evaluates the nature of a cellular response in a qualitative fashion. Stent implantation elicits a well documented cellular, healing response. The significant characteristics of the cellular response to stents include: damage to vascular structures, presence of inflammation, foreign body reaction, and cellular and tissue types preset in the neo-intimal response.
Morphometry evaluates the vascular structures and reaction to the stent in a quantitative manner. The areas of the different regions (i.e. medical area, neointimal area) are calculated and compared.
Microscopy of the excised tissue can be used to study the implantable drug delivery devices. Although pathologists gain some insight into the cellular response, they are limited to only what they can see visually in the tissue or stained tissue. Finding the implanted drug delivery devices under a microscope can be tedious and time consuming. In addition, actual molecular analysis of the tissue, such as the presence of the drug, diffusion of the drug, biochemical composition of the tissue, changes in the tissue due to the drug, and identification of fluid and cellular components, still remain a challenge. Therefore, other analytical alternatives are necessary to aid the pathologist in evaluation of tissue.
As biology research and clinical medicine both move toward a more molecular level of understanding, there is a growing need for tools, which can evaluate biological samples with sensitivity to subtle molecular differences, such as in the case of a drug delivery device implanted into a tissue. Because biological processes in cells and tissues occur through localized chemical changes in specific cells or subcellular structures, a spatial resolution of molecular distinctions is very useful, if not necessary.